Liquid, and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule. Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when relatively small amounts of an active are to be delivered. Additionally, soft gelatin capsules are aesthetically appealed (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
However, despite these advantages of liquid compositions, it is not always possible to prepare a liquid composition of the desired pharmaceutical active. Many pharmaceutical actives are poorly soluble and therefore require relatively large volumes of solvent for dissolution . Also, the choice of solvents available for use in liquid compositions is limited by safety, compatibility, stability, and economic concerns. Furthermore, the use of large volumes of solvents for solubilizing pharmaceutical actives is undesirable because the resulting solutions would be so dilute as to require impractically large dosages for delivering a therapeutically effective amount of active. It would thus be difficult, if not impossible, to encapsulate such large volumes into only one or two gelatin capsules and yet have them be of a reasonable size for easy swallowing.
One approach to overcoming these solubility problems has been to incorporate water, water-miscible co-solvents, and surfactants into the compositions. See, U.S. Pat. No. 4,794,117, to Corbiere, issued Dec. 27, 1988 which discloses the solubilization of hydrophobic pharmaceuticals in aqueous solutions of polyethylene glycol at controlled pH; U.S. Pat. No. 4,690,823, to Lohner at al, issued Sep. 1, 1987 which discloses the solubilization of ibuprofen in a mixture of polyethylene glycol and a surfactant; U.S. Pat. No. 3,784,684, to Bossert et al., issued Jan. 8, 1974 which discloses the solubilization of a pharmaceutical active in a mixture of polyethylene glycol and an alcohol having 2-8 carbons and 1-3 hydroxy groups; PCT Application No. W088/02625, to Yu et al., published Apr. 21, 1988 which discloses the solubilization of an ionized or partly-ionized pharmaceutical active in a mixture of water, polyethylene glycol, and polyvinylpyrrolidone; and European Patent Application No. 152,292, to Rogers, published Aug. 21, 1985 which discloses acetaminophen formulations containing polyethylene glycol, an acrylic acid resin, and a surfactant.
In many instances it may not be possible or desirable to incorporate water, water-miscible co-solvents, or surfactants into a pharmaceutical composition. For example, water-miscible co-solvents, such as ethanol, have the disadvantage of being relatively volatile, thereby resulting in concentration changes in the actives over time. Also, these co-solvents may not be compatible with the desired pharmaceutical actives. A more important disadvantage of water and volatile water-miscible co-solvents is that they are incompatible with soft gelatin capsules. Even though it may be possible to prepare soft gelatin capsules containing these solvents, over time the capsules gradually soften and deform, and develop leaks as these solvents dissolve the soft gelatin shell. Thus, it would be highly desirable to develop a solubilization process which does not require the use of water; and in processes where water-miscible co-solvents are used, it would be highly desirable to develop a process in which the water-miscible solvents are ultimately removed from the final compositions.
Previous investigators have attempted to circumvent these incompatibility problems by modifying the composition of the capsule shell. For example, U.S. Pat. No. 3,865,603, to Szymanski et al., issued Feb. 11, 1975 discloses gelatin compositions which are extended with chemically modified fluidity starches; U.S. Pat. No. 2,580,683, to Kreuger, issued Jan. 1, 1952 discloses gelatin compositions modified by the addition of non-hydroscopic water soluble substances; and Japanese Pat. No. 84044096, to Morishita, issued Jan. 26, 1984 discloses gelatin shells modified with tannic acid, and sugar and/or sugar derivatives. However, it may not always be desirable, feasible or economical to modify the soft gelatin shell with such additives. Thus, it would be highly desirable to find a solubilizing system for pharmaceutical actives which would also be compatible with soft gelatin shells.
Many processes for solubilizing pharmaceutical actives employ heat. However, heating the mixture is not always feasible or desirable because of stability concerns and the additional equipment, time, and costs associated with utilizing a heating process. Thus, it would be highly desirable to develop a solubilization process not requiring the use of heat.
The solubilization process of the present invention overcomes the disadvantages of the prior art by not requiring the use of water as a solvent, except for the minor amounts of water normally present in the materials employed and/or which is absorbed from the environment. Thus, the concentrated pharmaceutical compositions of the instant invention are substantially free of water. Importantly, the process of the present invention does not require a heating step.
It is therefore an object of the present invention to provide a process for solubilizing difficulty soluble pharmaceutical actives. Another object of the present invention is to provide a solubilization process which does not require water as a solvent or the use of a heating step. A further object of the present invention is to provide a process for preparing soft gelatin capsules containing a solution of a difficulty soluble pharmaceutical active, in which the soft gelatin shell is optionally transparent. A still further object of the present invention is to provide pharmaceutical compositions containing difficulty soluble pharmaceutical actives. As even further object of the present invention is to provide soft gelatin capsules containing a solution of a difficulty soluble pharmaceutical active, in which the soft gelatin shell is optionally transparent.
These and other objects of this invention will become apparent in light of the following disclosure.